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    Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy.

    Nat Commun 2014 May 13;5:3828. Epub 2014 May 13.
    Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
    Endosomal protein sorting controls the localization of many physiologically important proteins and is linked to several neurodegenerative diseases. VPS35 is a component of the retromer complex, which mediates endosome-to-Golgi retrieval of membrane proteins such as the cation-independent mannose 6-phosphate receptor. Furthermore, retromer is also required for the endosomal recruitment of the actin nucleation promoting WASH complex. The VPS35 D620N mutation causes a rare form of autosomal-dominant Parkinson's disease (PD). Here we show that this mutant associates poorly with the WASH complex and impairs WASH recruitment to endosomes. Autophagy is impaired in cells expressing PD-mutant VPS35 or lacking WASH. The autophagy defects can be explained, at least in part, by abnormal trafficking of the autophagy protein ATG9A. Thus, the PD-causing D620N mutation in VPS35 restricts WASH complex recruitment to endosomes, and reveals a novel role for the WASH complex in autophagosome formation.
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